Il-15-based fusions to il-12 and il-18

Abstract

The invention features multi-specific fusion protein complexes with one domain comprising IL-15 or a functional variant and a binding domain specific to IL-12 or IL-18.

1 .- 40 . (canceled) 
     
     
         41 . An isolated fusion protein complex comprising:
 a first soluble protein comprising an interleukin-15 (IL-15) polypeptide domain and a first immunoglobulin Fc polypeptide domain, and   a second soluble protein comprising a soluble IL-15 receptor alpha sushi (IL-15RαSu) polypeptide domain and a second immunoglobulin Fc polypeptide domain,   wherein the IL-15 polypeptide domain binds to the IL-15RαSu polypeptide domain to form the soluble fusion protein complex.   
     
     
         42 . The fusion protein complex of  claim 41 , wherein the IL-15 polypeptide is an IL-IS variant. 
     
     
         43 . The fusion protein complex of  claim 42 , wherein the IL-15 variant comprises an N72D mutation (IL-15N72D). 
     
     
         44 . The fusion protein complex of  claim 41 , wherein the Fc domain is selected from the group consisting of IgG Fc domain, human IgG1 Fc domain, human IgG2 Fc domain, human IgG3 Fc domain, human IgG4 Fc domain, IgA Fc domain, IgD Fc domain, IgE Fc domain, and IgM Fc domain. 
     
     
         45 . The fusion protein complex of  claim 41 , wherein the Fc domain of the first soluble protein is covalently linked to the Fc domain of the second soluble protein. 
     
     
         46 . The fusion protein complex of  claim 41 , wherein the Fc domain includes an amino acid change that results in an Fc domain with altered complement binding properties, altered Fc receptor binding properties, altered dimerization, or altered glycosylation profiles. 
     
     
         47 . The fusion protein complex of  claim 41 , wherein the first and second immunoglobulin Fc polypeptide domains are the same. 
     
     
         48 . The fusion protein complex of  claim 41 , wherein the first and second immunoglobulin Fc polypeptide domains are different. 
     
     
         49 . A method for stimulating an immune response, the method comprising:
 a. contacting plurality of immune cells with the fusion protein complex of claim  1 ;   b. activating the immune cells, and   c. contacting target disease cells with an effective amount of the activated immune cells.   
     
     
         50 . The method of  claim 49 , wherein the target disease cells are tumor cells or infected cells. 
     
     
         51 . The method of  claim 49 , wherein said immune cells are NK cells or cytokine induced memory like (CIML) NK cells. 
     
     
         52 . The method of  claim 49 , wherein said effective amount of the activated immune cells is between 1×10 4  cells/kg and 1×10 10  cells/kg. 
     
     
         53 . The method of  claim 49 , wherein said immune cells are administered at least one time per week. 
     
     
         54 . A method of preventing or treating a disease in a patient in need thereof, the method comprising:
 a. contacting a plurality of immune cells with the soluble fusion protein complex of claim  1 ;   b. activating the immune cells;   c. administering an effective amount of the activated immune cells to the patient, and   d. damaging or killing disease cells via the activated immune cells.   
     
     
         55 . The method of  claim 54 , wherein said disease is a neoplasia or infectious disease. 
     
     
         56 . A method for treating a neoplasia or infectious disease in a subject in need thereof comprising administering to said subject an effective amount of a pharmaceutical composition comprising the soluble fusion protein complex of claim  1 . 
     
     
         57 . The method of  claim 56 , wherein said effective amount is between about 1 and 100 pig/kg said fusion protein complex. 
     
     
         58 . The method of  claim 56 , wherein said neoplasia is selected from the group consisting of a glioblastoma, prostate cancer, hematological cancer, B-cell neoplasms, multiple myeloma, B-cell lymphoma, B cell non-Hodgkin lymphoma, Hodgkin's lymphoma, chronic lymphocytic leukemia, acute myeloid leukemia, cutaneous T-cell lymphoma, T-cell lymphoma, a solid tumor, urothelial/bladder carcinoma, melanoma, lung cancer, renal cell carcinoma, breast cancer, gastric and esophageal cancer, prostate cancer, pancreatic cancer, colorectal cancer, ovarian cancer, non-small cell lung carcinoma, and squamous cell head and neck carcinoma. 
     
     
         59 . A method of making the soluble fusion protein complex of claim  1 , the method comprising introducing into a host cell a DNA vector encoding the first and second soluble proteins, culturing the host cell in media under conditions sufficient to express the fusion proteins in the cell or the media and allow association between IL-15 domain of a first soluble protein and the IL-15Rα domain of a second soluble protein to form the fusion protein complex, and purifying the fusion protein complex from the host cells or media.